The present invention relates to enhancing the inhibition of T-cell proliferation in a mammalian host and especially a human host. More particularly, the present invention is concerned with enhancing the inhibition of T-cell proliferation by administering 2xe2x80x2-deoxyguanosine and/or prodrugs thereof and certain PNP inhibitors which significantly prolong the half-life of the 2xe2x80x2-deoxyguanosine in a host. The PNP inhibitors employed according to the present invention possess Ki value of 50 nanomoles or less. The process of the present invention enhances the selective inhibition of T-cell proliferation without damaging humoral immunity, which renders the process potentially effective against disorders in which T-cells are pathogenic.
Purine nucleoside phosphorylase (PNP) deficiency is a rare inherited disease accounting for approximately 4% of patients with severe combined immunodeficiency. In PNP deficiency, T- and B-cell immunity are affected. T-cell function may be profoundly deficient, may be normal at birth and then decrease with time, or may fluctuate repeatedly between low and normal. B-cell function can be normal but is deficient in approximately one third of patients. PNP protein is a trimer of approximately 90,000 daltons. It is found in most tissues of the body but is at highest levels in lymphoid tissues. This tissue distribution explains why the lymphoid system is predominantly affected in PNP deficiency. Many mechanisms have been proposed to explain the metabolic toxicity in PNP deficiency. The elevated dGTP found in PNP deficiency is thought to inhibit ribonucleotide reductase and, thus, impede cell division.
8-Aminoguanine given with 2xe2x80x2-deoxyguanosine inhibits the proliferation of human T-cells (CCRF-CEM and Molt-4 cells) in cultures. 8-Aminoguanosine, a soluble derivative which is converted in vivo to 8-aminoguanine, given to rats and dogs with 2xe2x80x2-deoxyguanosine causes a profound fall in peripheral blood lymphocytes and was shown in rats to produce increased levels of 2xe2x80x2-deoxyguanosine triphosphate (dGTP) in T-cells. To produce lymphopenia, inhibition of PNP was required, since 2xe2x80x2-deoxyguanosine alone did not significantly decrease cell counts.
9-(3-Pyridylmethyl)-9-deazaguanine, one of a family of PNP inhibitors, increases plasma inosine levels in humans, indicating effective inhibition of PNP, but it did not reduce T-cell counts. The cell culture and animal data presented above would indicate that in order to inhibit T-cell proliferation in humans, it would be necessary to provide exogenous 2xe2x80x2-deoxyguanosine, which would cause a sufficient accumulation of dGTP exclusively in the T-cells to inhibit their proliferation. However, exogenous 2xe2x80x2-deoxyguanosine rapidly degrades upon being administered to a host and therefore is not effective when administered alone.
It has been found according to the present invention that administering certain PNP inhibitors in addition to the exogenous 2xe2x80x2-deoxyguanosine and/or prodrug of 2xe2x80x2-deoxyguanosine results in significantly prolonging the half-life of the 2xe2x80x2-deoxyguanosine. Therefore, the combination of 2xe2x80x2-deoxyguanosine and/or prodrug of 2xe2x80x2-deoxyguanosine and the PNP inhibitors employed according to the present invention provides a potentially effective treatment against disorders in which activated T-cells are pathogenic. For instance, the implication of T-cells in the pathogenesis of various autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, psoriasis and type 1 diabetes strongly suggests that the present invention will be an effective therapy for these diseases. Other indications are the prevention of organ transplant rejection and the treatment of T-cell lymphomas and leukemias.
The PNP inhibitors employed according to the present invention have a Ki value of 50 nanomoles or less. The PNP inhibitor can be administered along with or prior to the 2xe2x80x2-deoxyguanosine and/or prodrug of 2xe2x80x2-deoxyguanosine.
Still other objects and advantages of the present invention will become readily apparent by those skilled in the art from the following detailed description, wherein it is shown and described only the preferred embodiments of the invention, simply by way of illustration of the best mode contemplated of carrying out the invention. As will be realized the invention is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, without departing from the invention. Accordingly, the description is to be regarded as illustrative in nature and not as restrictive.
The present invention relates to enhancing the inhibition of T-cell proliferation in a mammalian host in need of such treatment and especially a human host an effective amount of 2xe2x80x2-deoxyguanosine and/or prodrug of 2xe2x80x2-deoxyguanosine and an effective amount of at least one PNP inhibitor. The PNP inhibitor employed according to the present invention has a Ki value of 50 nanomoles or less.
Examples of suitable PNP inhibitors employed according to the present invention are those disclosed in U.S. Pat. Nos. 4,985,433; 4,985,434, 5,008,265; 5,008,270; 5,565,463 and 5,721,240 assigned to BioCryst Pharmaceuticals, Inc., disclosures of which are incorporated herein by reference. The preferred PNP inhibitor employed according to the present invention is 9-(3-pyridylmethyl)-9-deazaguanine.